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Ron Shapiro, MD
Minimizing Toxicity, Maximizing Efficacy: The Search Continues
The side effects associated with conventional immunosuppression have driven the search for new agents that minimize toxicities and maximize immunosuppressive efficacy. The studies reported in this session included a variety of agents, many of which remain investigational.

Bioflavonoids
Bioflavonoids, found in the rinds of green citrus fruits, rose hips, and black currants, improve the uptake and utilization of vitamin C, and as antioxidants are known to be protective against cancer, heart disease, and other chronic diseases. Two bioflavonoids, curcumin and quercetin, are being investigated as novel adjuvant agents for immunosuppression in transplant recipients. Curcumin is a dietary pigment in curry with known antineoplastic and anti-inflammatory effects. Quercetin, which is primarily found in apples, onions, and black tea, is a plant pigment that serves as a building block for other members of the flavonoid family.

Shoskes and colleagues,[1] of Weston, Florida, examined the effects of 2 bioflavonoids, curcumin and quercetin, on early graft function in a randomized, placebo-controlled trial of cadaveric renal transplant recipients. Curcumin and quercetin are natural antioxidants that apparently block tyrosine kinase, nitric oxide enzymes, and NF-kB-mediated inflammation, and induce hemoxygenase-1. They are marketed as Oxy-Q, which contains 480 mg of curcumin and 20 mg of quercetin. Forty-three patients were randomized to placebo, low-dose Oxy-Q (1 pill daily and 1 placebo), or high-dose Oxy-Q (1 pill twice daily). Immunosuppression was with daclizumab, mycophenolate mofetil (MMF), and corticosteroids (steroids). Delayed graft function was observed in 13% of the placebo group and in none of the low-dose or high-dose Oxy-Q groups. Slow graft function was observed in 47% of the placebo group, 29% of the low-dose group, and 7% of the high-dose group. Renal function was better in the high-dose group (1.3 mg/dL at 30 days) than in the low-dose group (1.7 mg/dL) or the placebo group (1.8 mg/dL). Acute rejection was observed in 13% of the placebo and low-dose groups, and in 0% of the high-dose group. Tremor was observed in 13% of the high-dose group and 43% of the low-dose and placebo groups. Urinary hemoxygenase-1 levels were elevated in patients receiving the bioflavonoids. The findings in this small study were intriguing, although a bit difficult to understand. It would be interesting to study these agents in a larger group of patients.

LEA29Y
The novel biological agents being developed for induction therapy are being designed to reduce dependence on nephrotoxic agents, improve outcome, and facilitate the emergence of tolerance. The fusion receptor protein LEA29Y, a second-generation CTLA4Ig, is one such agent.

Renal transplant recipients were enrolled in a randomized trial of belatacept (LEA29Y), an investigational costimulation blocker. All patients received basiliximab, MMF, and steroids, and were randomized to high-intensity belatacept (n = 17), low-intensity belatacept (n = 16), or cyclosporine (CsA, n = 10). The study by Grinyo and colleagues,[2] of Barcelona, Spain, focused on outcomes in recipients of high-risk kidneys (ie, donors over 60 years of age, cold ischemia time > 24 hours, or cases of delayed or slow graft function). The numbers in these subgroups were small; however, patients receiving belatacept had better renal function at 6 months and a lower incidence of chronic allograft nephropathy, with no difference in patient survival, graft survival, or incidence of acute rejection. Although this agent is given parenterally at various time points after transplantation, its advantages, if borne out in phase 3 trials, may outweigh the disadvantages of intermittent intravenous therapy.

Rituximab
Rituximab is a high-affinity CD20-specific antibody that inhibits B-cell proliferation while inducing cellular apoptosis. Thus, it is a rational choice for therapy in transplantation to abrogate B-cell-mediated events. Two studies examined various aspects of rituximab, a chimeric anti-CD20 monoclonal antibody. One study, from the Karolinska Institute in Sweden,[3] studied 31 patients and found long-lasting B-cell depletion, extending beyond 1 year. The other, from NewYork-Presbyterian Hospital, New York, NY,[4] looked at the efficacy of rituximab in 6 patients with humoral rejection who also received pheresis and intravenous immune globulin (IVIG); 6 patients received pheresis, IVIG, steroids, and either OKT3 or rabbit antithymocyte globulin. Five of the rituximab-treated patients kept their allografts, compared with 2 of the conventionally treated patients. Both studies suggest that there is clearly a role for rituximab in the transplant armamentarium.

FTY720
FTY720, a novel immunomodulator that has proven effective in animal models of transplantation and autoimmunity, has achieved promising results in phase 1 and phase 2 studies of renal transplantation in humans, and is currently undergoing phase 3 studies. FTY720 is the first of a new drug class: sphingosine-1-phosphate receptor agonist. Its effect relates to the modulation of lymphocytes trafficking from blood and peripheral tissues to the lymph nodes. Unlike conventional immunosuppressants, FTY720 does not impair the activation, proliferation, or effector functions of T and B cells.

Four reports included discussions on various aspects of FTY720, an investigational and novel sphingosine-1-phosphate receptor agonist. Two of the studies looked at bradycardia[5,6] and concluded that multiple doses of 1.25 mg or 5 mg daily, or single doses of 5-40 mg, did not have any progressive or additional effects on bradycardia in healthy volunteers. Another study looked at the dose effect on lymphocyte count and rejection rate, and concluded that doses of 2.5 mg or 5 mg daily were associated with the highest FTY levels, the lowest rejection rates, and the greatest degree of lymphocyte depletion.[7] Another study looked at lymphocyte subset depletion and concluded that T cells were more depleted than B cells.[8] There is a great deal of interest in FTY720 as an immunosuppressive agent, and the outcomes of the phase 3 trials will be awaited with great anticipation.

KRP-203
A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. Satomi Iwai, of Tochigi, Japan, described a novel sphingosine-1-phosphate receptor agonist, KRP-203, that more selectively targets P1 receptors found on lymphocytes compared with P3 receptors found in the heart (and which presumably mediate bradycardia).[9] In experimental studies of rat kidney transplantation, the combination of KRP-203 and low-dose CsA was found to be associated with comparable survival but better renal function, less tubulitis, and better weight gain. Large animal studies have apparently also been performed to validate the efficacy seen in small animals, and clinical trials are pending. A selective FTY720-like agent with less bradycardia and comparable immunosuppressive efficacy may represent an important breakthrough in this class of compounds.

Taken together, the studies reported in this session represent encouraging signs that novel immunosuppressive agents are in the pipeline and that the future continues to suggest ongoing progress in immunosuppression.

References
Shoskes DA, Lapierre C, Muruve N, et al. Quercetin and circumin improve early graft function in cadaveric renal transplantation: a randomized placebo controlled trial. Program and abstracts of the American Transplant Congress 2005: 6th Annual Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation; May 21-25, 2005; Seattle, Washington. Abstract 945.
Grinyo J, Halloran P, Vanrenterghem Y, et al. Belatacept (LEA 29Y) as part of a CNI-free regimen in recipients of renal allografts with higher risk of poor long-term function and graft loss: comparison with cyclosporine A. Program and abstracts of the American Transplant Congress 2005: 6th Annual Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation; May 21-25, 2005; Seattle, Washington. Abstract 946.
Genberg H, Hansson A, Wernerson A, Tyden G. Effective B-cell depletion in peripheral blood and tissue by single-dose rituximab in kidney transplant recipients: a pilot study. Program and abstracts of the American Transplant Congress 2005: 6th Annual Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation; May 21-25, 2005; Seattle, Washington. Abstract 948.
Goldstein MJ, Lee S, Guarrera JV, Cohen DJ, Hardy A. Rituximab rescue for refractory antibody-mediated rejection after kidney transplantation. Program and abstracts of the American Transplant Congress 2005: 6th Annual Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation; May 21-25, 2005; Seattle, Washington. Abstract 949.
Schmouder R, DiMarco J, Serra D, et al. FTY 720 multiple dosing does not result in progressive reduction of heart rate. Program and abstracts of the American Transplant Congress 2005: 6th Annual Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation; May 21-25, 2005; Seattle, Washington. Abstract 950.
Dlade A, Kovarik J, Hunt T, Schmouder R. FTY 720 heart rate reduction: doses from 5 mg to 40 mg do not result in any greater heart rate effect. Program and abstracts of the American Transplant Congress 2005: 6th Annual Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation; May 21-25, 2005; Seattle, Washington. Abstract 952.
Kovarik JM, Tedesco H, Mulgaonkar S, Picard F, Schmouder RL. FTY 720 exposure-response relationships linking blood levels, lymphocytes, and efficacy in kidney transplantation. Program and abstracts of the American Transplant Congress 2005: 6th Annual Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation; May 21-25, 2005; Seattle, Washington. Abstract 951.
Boehler T, Schuetz M, Budde K, Neumayer HH, Waiser J. Effect of FTY 720 on peripheral B-lymphocyte subpopulations in human stable renal transplant patients. Program and abstracts of the American Transplant Congress 2005: 6th Annual Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation; May 21-25, 2005; Seattle, Washington. Abstract 953.
Iwai S, Fujishiro J, Kudou S, et al. Abrogation of renal allograft rejection by KRP-203, a novel sphingosine-1-phosphate receptor agonist, with subtherapeutic dose of cyclosporine A. Program and abstracts of the American Transplant Congress 2005: 6th Annual Joint Meeting of the American Society of Transplant Surgeons and the American Society of Transplantation; May 21-25, 2005; Seattle, Washington. Abstract 947.

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Interesting....I just posted on the effects of Bioflavonoids in the Dark red bitter wines such as Merlot. I am not at all advocating that people should rush out and get drunk on Merlot, However it is reccomended by heart dr.'s and my MS specialist said a glass or two a month would be helpful.

Now, this also has to take into account what symptom meds you are on. With most you should not drink any alchohol. I am on some of those at night, so if a have a glass I try to make it during the day.........Kim

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